The present invention relates to a novel process for preparing known, optically active amines which can be employed as intermediates for preparing pharmaceuticals and crop protection agents. Moreover, the invention relates to novel optically active acylated amines.
It is already known from DE-A 4 332 738 that optically active, primary and secondary amines can be prepared by initially enantioselectively acylating racemic amine in the presence of a hydrolase using an ester which has an electron-rich heteroatom in the acid moiety in the vicinity of the carbonyl carbon atom, then separating the resulting mixture of optically active (S)-amine and optically active acylated (R)-amine (=amide), thereby affording the (S)-amine, and obtaining the other enantiomer, if desired, from the acylated (R)amine by amide cleavage. Suitable hydrolases are lipases from Pseudomonas, for example Amano P, or from Pseudomonas spec. DSM 8246. The degree of optical purity of the enantiomers that are obtained is very high. However, this process has the disadvantages that relatively long reaction times are required for the enzymatic acylation and that the reaction is carried out in highly dilute solution. Only after relatively long reaction times is the remaining (S)-enantiomer obtained in sufficiently high optical yield. For practical purposes, the space-time yields that can be achieved are therefore inadequate. It is a further disadvantage that relatively high amounts of enzyme are required with respect to the substrate. Besides, the enzyme has very high activity, so that purification, concentration and work-up requires considerable effort.
Furthermore, Chimica 48, 570 (1994) discloses that racemic amines will react enantioselectively with ethyl acetate in the presence of lipase from Candida antarctica to give mixtures of (S)-amine and acetylated (R)-amine (=amide) from which (S)-amine and acetylated (R)-amine can be isolated, it being possible to set free the acetylated (R)-amine by subsequent amide cleavage. Disadvantages of this method are that once more relatively long reaction times are required and that furthermore the yields are not always satisfactory. In addition, the ratio of enzyme to substrate is again so disadvantageous that an economical utilization of the process is scarcely possible.
It has now been found that optically active amines of the formula 
in which
R represents aryl which is optionally mono- to trisubstituted by identical or different substituents, but where the positions of the aryl group which are adjacent to the linking point do not carry any substituents, or
xe2x80x83represents optionally benzo-fused heteroaryl which is optionally mono- to trisubstituted by identical or different substituents, but where the positions of the heteroaryl group which are adjacent to the linking point do not carry any substituents, or
xe2x80x83represents alkyl having 1 to 7 carbon atoms, halogenoalkyl having 1 to 7 carbon atoms and 1 to 5 halogen atoms or alkoxyalkyl having 1 to 7 carbon atoms in the alkyl moiety and 1 to 3 carbon atoms in the alkoxy moiety, and
m represents the numbers 0, 1, 2 or 3,
are obtained by
a) reacting, in a first step, racemic amines of the formula 
in which
R and m are each as defined above,
with esters of the formula 
xe2x80x83in which
R1 represents alkyl having 1 to 10 carbon atoms or represents halogenoalkyl having 1 to 6 carbon atoms and 1 to 5 halogen atoms,
R2 represents hydrogen, alkyl having 1 to 10 carbon atoms, halogenoalkyl having 1 to 6 carbon atoms and 1 to 5 halogen atoms or represents phenyl which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxyl, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, phenyl and phenoxy,
X represents oxygen, sulphur or an -NR3- group in which
R3 represents alkyl having 1 to 4 carbon atoms, and
n represents the numbers 0, 1, 2 or 3,
xe2x80x83in the presence of lipase from Candida antarctica and, if appropriate, in the presence of a diluent,
b) separating, in a second step, the resulting mixture of (S)-amine of the formula 
in which
R and m are each as defined above,
and acylated (R)-amine of the formula 
xe2x80x83in which
R, R2, X, m and n are each as defined above, and
c) if appropriate, setting free, in a third step, the (R)-amine of the formula 
in which
R and m are each as defined above,
from the acylated (R)-amine of the formula (III) by treatment with acid or base, if appropriate in the presence of a diluent.
(R)-amines are understood to mean those optically active compounds of the formula (I) which exhibit the (R) configuration at the asymmetrically substituted carbon atom. Correspondingly, (S)-amines are understood to mean those optically active compounds of the formula (I) which exhibit the (S) configuration at the chiral centre. In the formulae, the asymmetrically substituted carbon atom is in each case indicated by (*).
It is extremely surprising that optically active amines of the formula (I*) can be prepared in high yield and very good optical purity by the process according to the invention. From the known prior art, it could not be foreseen that the specific use of lipase from Candida antarctica effects a high enantioselectivity and a faster reaction in the reaction between amine and ester than the enzyme systems used hitherto in similar processes.
The process according to the invention enjoys a number of advantages. Thus, it makes possible the preparation of a large number of optically active amines in high yield and excellent optical purity. It is also favourable that the reaction can be carried out at relatively high substrate concentration and that the reaction times are short. It is therefore possible to achieve space-time yields which are satisfactory even for practical purposes. It is a further advantage that the biocatalyst required is available in relatively large amounts and that it is stable even at elevated temperatures. In terms of the amount of enzyme relative to the substrate, the biocatalyst is employed in a relatively low amount and low enzyme activity. Finally, no difficulties are involved in carrying out the reaction and isolating the desired substances, namely either the (S)- or the (R)-amines.
If racemic 1-(4-chlorophenyl)-ethylamine is reacted with methyl methoxyacetate in the presence of lipase from Candida antarctica, the resulting components are separated and the (R)-enantiomer of N-[1-(4-chlorophenyl)ethyl]-methoxyacetamide is treated with hydrochloric acid, the course of the process according to the invention can be illustrated by the equation that follows. 
The formula (I) provides a general definition of the racemic amines required as starting materials for carrying out the process according to the invention.
R preferably represents optionally substituted phenyl of the formula 
in which
xe2x80x83R4, R5 and R6 independently of one another each represent hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, halogenoalkoxy having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, cyano, dialkylamino having 1 to 4 carbon atoms in each alkyl group, nitro, phenyl, phenoxy or benzyl, or
R represents naphthyl which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon and 1 to 5 identical or different halogen atoms, alkoxy having 1 to 4 carbon atoms and halogenoalkoxy having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, but where the positions ortho to the carbon atom through which the naphthyl radical is bonded are unsubstituted, or
R represents optionally benzo-fused heteroaryl having 5 or 6 ring members and 1 to 3 heteroatoms, such as nitrogen, oxygen and/or sulphur, in the heterocycle, where these radicals may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms and halogenoalkyl having 1 to 4 carbon atoms, but where the positions of the heteroaryl group which are adjacent to the linking point do not carry any substituents, or
xe2x80x83represents straight-chain or branched alkyl having 1 to 7 carbon atoms, halogenoalkyl having 1 to 5 carbon atoms and 1 to 5 fluorine and/or chlorine atoms or represents alkoxyalkyl having 1 to 5 carbon atoms in the alkyl moiety and, 1 to 3 carbon atoms in the alkoxy moiety.
m also preferably represents the numbers 0, 1, 2 or 3.
Particular preference is given to amines of the formula (I) in which
R represents optionally substituted phenyl of the formula 
in which
xe2x80x83R4, R5 and R6 independently of one another each represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, methoxy, ethoxy, methylthio, trichloromethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluorochloromethoxy, difluoromethoxy, cyano, dimethylamino, diethylamino, nitro, phenyl, phenoxy or benzyl, or
R represents naphthyl which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, methoxy, ethoxy, trichloromethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluorochloromethoxy and difluoromethoxy, but where the positions ortho to the carbon atom through which the naphthyl radical is bonded are not substituted, or
R represents optionally benzo-fused furyl, thienyl, pyridyl or pyrimidine, where these radicals may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, trifluoromethyl and trifluoroethyl, but where the positions of the heteroaryl group which are adjacent to the linking point do not carry any substituents, or
R represents straight-chain or branched alkyl having 1 to 5 carbon atoms, halogenoalkyl having 1 to 5 carbon atoms and 1 to 3 fluorine and/or chlorine atoms or represents alkoxyalkyl having 1 to 3 carbon atoms in the alkyl moiety and 1 to 3 carbon atoms in the alkoxy moiety and
m represents the numbers 0, 1 or 2.
Examples of amines of the formula (I) include the compounds of the formulae that follow: 
The racemic amines of the formula (I) are known or can be prepared by known methods.
The formula (II) provides a general definition of the esters required as reaction components for carrying out the first step of the process according to the invention.
R1 preferably represents straight-chain alkyl having 1 to 8 carbon atoms or represents straight-chain halogenoalkyl having 1 to 4 carbon atoms and 1 to 3 fluorine and/or chlorine atoms,
R2 preferably represents hydrogen, straight-chain alkyl having 1 to 8 carbon atoms, straight-chain halogenoalkyl having 1 to 4 carbon atoms and 1 to 3 fluorine, chlorine and/or bromine atoms, or represents phenyl which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, methyl, ethyl, methoxy, ethoxy, phenyl and phenoxy.
X preferably represents oxygen or sulphur.
n preferably represents the numbers 0, 1 or 2.
Particular preference is given to esters of the formula (II) in which
R1 represents methyl, ethyl, n-propyl, n-butyl, chloromethyl, 2-chloroethyl, 2-fluoroethyl or 2,2,2-trifluoroethyl,
R2 represents hydrogen, methyl, ethyl, n-propyl, n-butyl, chloromethyl, trifluoromethyl, 2-chloroethyl or represents phenyl which is optionally mono- or disubstituted by fluorine, chlorine, bromine, amino, hydroxyl, methyl, ethyl, methoxy, phenyl and/or phenoxy,
X represents oxygen or sulphur and
n represents the numbers 1 or 2.
Examples of esters of the formula (II) include the compounds of the formulae that follow. 
The esters of the formula (II) are known or can be prepared by known methods.
The biocatalyst used for carrying out the first step of the process according to the invention is lipase from Candida antarctica. Preference is given to using the product which is commercially available under the name Novozym 435(copyright).
The lipase can be employed either in native or in modified form, for example microencapsulated or bound to inorganic or organic support materials. Examples of support materials which are suitable in this context are Celite, Lewatit, zeolites, polysaccharides, polyamides and polystyrene resins.
Suitable diluents for carrying out the first step of the process according to the invention are all organic solvents which are customary for such reactions. Preference is given to using ethers, such as methyl tert-butyl ether or tert-amyl methyl ether, furthermore aliphatic or aromatic hydrocarbons, such as hexane, cyclohexane or toluene, additionally nitrites, such as acetonitrile or butyronitrile, moreover alcohols, such as tert-butanol or 3-methyl-3-pentanol, and finally also the esters used for the acylation.
When carrying out the first step of the process according to the invention, the temperatures can be varied within a certain range. In general, the reaction is carried out at temperatures between 0xc2x0 C. and 80xc2x0 C., preferably between 10xc2x0 C. and 60xc2x0 C.
The first step of the process according to the invention is generally carried out under atmospheric pressure, if appropriate under an inert gas such as nitrogen or argon.
When carrying out the first step of the process according to the invention, generally 0.6 to 10 mol, preferably 1 to 3 mol of ester of the formula (II) are employed per mole of racemic amine of the formula (I). The amount of lipase can also be varied within a certain range. In general, 1 to 10% by weight of immobilized lipase, based on racemic amine, are employed, corresponding to an activity of 10,000 to. 112,000 units of lipase per mole of racemic amine. Specifically, the first step of the process according to the invention is carried out in such a manner that the components are added in any order and the resulting mixture is stirred at the particular reaction temperature until the desired conversion has been achieved. To terminate the reaction, the biocatalyst is generally removed by filtration.
In the second step, the mixture obtained in the first step of the process according to the invention is worked up by customary methods. Generally, the desired components are isolated by distillation, fractional crystallization, acid-base solvent extraction or by other means. Thus, it is for example possible to subject the reaction mixture to fractional distillation. It is also possible to concentrate the reaction mixture, to take up the residue that remains in an organic solvent which is sparingly miscible with water, to treat the resulting solution with water and mineral acid and to separate the phases. Concentration of the organic phase affords the acylated (R)-amine. The (S)-amine can be isolated from the aqueous phase by initial treatment with base, subsequent extraction with an organic solvent which is sparingly miscible with water and drying and concentration of the combined organic phases. - If appropriate, the isolated products can be purified further, for example by chromatography or distillation.
The acylated (R)-amines of the formula 
in which
R8 represents fluorine, chlorine, bromine, methyl, methoxy or methylthio,
R7 and R9 each represent hydrogen and
p represents the numbers 0, 1 or 2, or
R8 represents hydrogen,
R7 and R9 each represent methyl and
p represents 2,
are novel.
Examples of acylated (R)-amines of the formula (IIIa) include the compounds of the following formulae: 
Suitable acids for carrying out the third step of the process according to the invention are all customary strong acids. Those which are preferably utilizable are mineral acids, such as sulphuric acid or hydrochloric acid.
Suitable bases for carrying out the third step of the process according to the invention are all customary strong bases. Those which are preferably utilizable are inorganic bases, such as sodium hydroxide or potassium hydroxide.
Suitable diluents for carrying out the third step of the process according to the invention are all organic solvents which are customary for such reactions, and water. Those which are preferably utilizable are water or mixtures of water and organic solvents, examples including mixtures of water and toluene.
When carrying out the third step of the process according to the invention, the temperatures may be varied within a relatively wide range. In general, the reaction is carried out at temperatures between 20 and 180xc2x0 C., preferably between 30 and 150xc2x0 C.
The third step of the process according to the invention is generally carried out under atmospheric pressure. However, it is also possible to work under elevated or reduced pressure
When carrying out the third step of the process according to the invention, generally 1 to 5 equivalents or else a larger excess of acid or base are employed per mole of acylated (R)-amine of the formula (III). Work-up is carried out by customary methods. In general, after the cleavage has ended and after neutralization, the reaction mixture is extracted with an organic solvent which is sparingly miscible with water, and the combined organic phases are dried and concentrated. If appropriate, the resulting product can be freed from impurities which may still be present using customary methods.
The amines of the formula (I*) preparable by the process according to the invention are useful intermediates for preparing pharmaceuticals or active compounds having insecticidal, fungicidal or herbicidal properties (cf EP-A 0 519 211, EP-A 0 453 137, EP-A 0 283 879, EP-A 0 264 217 and EP-A 0 341 475). Thus, for example, the fungicidally active compound of the formula 
is obtained by reacting (R)-1-(4-chloro-phenyl)-ethylamine of the formula 
with 2,2-dichloro-1-ethyl-3-methyl-1-cyclopropanecarbonyl chloride of the formula 
in the presence of an acid binder and in the presence of an inert organic diluent.
The examples that follow illustrate the practice of the process according to the invention.